The effect and mechanism of Grim 19 on mouse sperm quality and testosterone synthesis

in Reproduction
Authors:
Yue ZhaoCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Haoran LiuCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Yang YangCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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https://orcid.org/0000-0002-4894-8816
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Wenqian HuangCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Lan ChaoCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Correspondence should be addressed to L Chao; Email: qlszcl@163.com
DOI:
https://doi.org/10.1530/REP-21-0385
Volume/Issue:
Volume 163: Issue 6
Page Range:
365–377
Article Type:
Research Article
Online Publication Date:
19 May 2022
Copyright:
© Society for Reproduction and Fertility 2022
Restricted access

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Abnormal sperm parameters such as oligospermia, asthenospermia, and teratozoospermia result in male factor infertility. Previous studies have shown that mitochondria play an important role in human spermatozoa motility. But the related pathogenesis is far from elucidated. The aim of this study was to investigate the association between gene associated with retinoid-interferon-induced mortality 19 (GRIM19) and asthenospermia. In this study, Grim19 knockout model (Grim19+/− mouse) was created through genome engineering. We showed that compared with WT mice, the sperm count and motility of Grim19+/− mice were significantly reduced. Grim19 may contribute to sperm count and vitality by influencing the mitochondrial membrane potential, intracellular reactive oxygen species production, and increasing cell apoptosis. The spermatogenic cells of all levels in the lumen of the seminiferous tubules were sparsely arranged, and the intercellular space became larger in the testis tissue of Grim19+/− mice. The serum testosterone concentration is significantly reduced in Grim19+/− mice. The expression of steroid synthesis-related proteins STAR, CYP11A1, and HSD3B was decreased in Grim19+/− mice. To further confirm whether changes in testosterone biosynthesis were due to Grim19 downregulation, we validated this result using Leydig cells and TM3 cells. We also found that Notch signaling pathway was involved in Grim19-mediated testosterone synthesis to some extent. In conclusion, we revealed a mechanism underlying Grim19 mediated spermatozoa motility and suggested that Grim19 affected the synthesis of testosterone and steroid hormones in male mouse partly through regulating Notch signal pathways.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Aghazadeh Y, Zirkin BR & Papadopoulos V 2015 Pharmacological regulation of the cholesterol transport machinery in steroidogenic cells of the testis. In Hormones and Transport Systems. Elsevier. (https://doi.org/10.1016/bs.vh.2014.12.006)

    • Search Google Scholar
    • Export Citation

  • Aitken RJ & Drevet JR 2020 The importance of oxidative stress in determining the functionality of mammalian spermatozoa: a two-edged sword. Antioxidants 9 111. (https://doi.org/10.3390/antiox9020111)

    • Search Google Scholar
    • Export Citation

  • Alamo A, De Luca C, Mongioì LM, Barbagallo F, Cannarella R, La Vignera S, Calogero AE & Condorelli RA 2020 Mitochondrial membrane potential predicts 4-hour sperm motility. Biomedicines 8 196. (https://doi.org/10.3390/biomedicines8070196)

    • Search Google Scholar
    • Export Citation

  • Angell JE, Lindner DJ, Shapiro PS, Hofmann ER & Kalvakolanu DV 2000 Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-β and retinoic acid combination, using a genetic approach. Journal of Biological Chemistry 275 33416–33426. (https://doi.org/10.1074/jbc.M003929200)

    • Search Google Scholar
    • Export Citation

  • Chao L, Wang X, Yang Y, Cui W, Xu J, Chen H, Hao A & Deng X 2015 Downregulation of gene expression and activity of GRIM-19 affects mouse oocyte viability, maturation, embryo development and implantation. Journal of Assisted Reproduction and Genetics 32 461–470. (https://doi.org/10.1007/s10815-014-0413-y)

    • Search Google Scholar
    • Export Citation

  • Chen M, Wang X, Wang Y, Zhang L, Xu B, Lv L, Cui X, Li W & Gao F 2014 Wt1 is involved in Leydig cell steroid hormone biosynthesis by regulating paracrine factor expression in mice. Biology of Reproduction 90 71. (https://doi.org/10.1095/biolreprod.113.114702)

    • Search Google Scholar
    • Export Citation

  • Chen H, Deng X, Yang Y, Shen Y, Chao L, Wen Y & Sun Y 2015 Expression of GRIM-19 in missed abortion and possible pathogenesis. Fertility and Sterility 103 138 .e3–14 6 .e3. (https://doi.org/10.1016/j.fertnstert.2014.10.012)

    • Search Google Scholar
    • Export Citation

  • Colvin JS, Green RP, Schmahl J, Capel B & Ornitz DM 2001 Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104 875–889. (https://doi.org/10.1016/s0092-8674(0100284-7)

    • Search Google Scholar
    • Export Citation

  • Dubé C & Tremblay J 2007 Characterization of the platelet-derived growth factor receptor alpha (PDGF-Rα) promoter in mouse Leydig cells. Biology of Reproduction 77 118–119. (https://doi.org/10.1093/biolreprod/77.s1.118b)

    • Search Google Scholar
    • Export Citation

  • Durairajanayagam D, Singh D, Agarwal A & Henkel R 2021 Causes and consequences of sperm mitochondrial dysfunction. Andrologia 53 e13666. (https://doi.org/10.1111/and.13666)

    • Search Google Scholar
    • Export Citation

  • Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE & Hirst J 2001 GRIM-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (complex I). Journal of Biological Chemistry 276 38345–38348. (https://doi.org/10.1074/jbc.C100444200)

    • Search Google Scholar
    • Export Citation

  • Ferramosca A, Provenzano SP, Coppola L & Zara V 2012 Mitochondrial respiratory efficiency is positively correlated with human sperm motility. Urology 79 809–814. (https://doi.org/10.1016/j.urology.2011.12.042)

    • Search Google Scholar
    • Export Citation

  • Grandbarbe L, Michelucci A, Heurtaux T, Hemmer K, Morga E & Heuschling P 2007 Notch signaling modulates the activation of microglial cells. Glia 55 1519–1530. (https://doi.org/10.1002/glia.20553)

    • Search Google Scholar
    • Export Citation

  • Hedger MP & Eddy EM 1986 Monoclonal antibodies against rat Leydig cell surface antigens. Biology of Reproduction 35 1309–1319. (https://doi.org/10.1095/biolreprod35.5.1309)

    • Search Google Scholar
    • Export Citation

  • Ho HJ, Shirakawa H, Yoshida R, Ito A, Maeda M, Goto T & Komai M 2016 Geranylgeraniol enhances testosterone production via the cAMP/protein kinase A pathway in testis-derived I-10 tumor cells. Bioscience, Biotechnology, and Biochemistry 80 791–797. (https://doi.org/10.1080/09168451.2015.1123612)

    • Search Google Scholar
    • Export Citation

  • Huang G, Lu H, Hao A, Ng DCH, Ponniah S, Guo K, Lufei C, Zeng Q & Cao X 2004 GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I. Molecular and Cellular Biology 24 8447–8456. (https://doi.org/10.1128/MCB.24.19.8447-8456.2004)

    • Search Google Scholar
    • Export Citation

  • Kapoor S 2013 Grim-19 expression and its close association with tumor progression in systemic malignancies. Gene 517 240. (https://doi.org/10.1016/j.gene.2013.01.012)

    • Search Google Scholar
    • Export Citation

  • Lafferty K, Allan K, Saravelos S & Raglan O 2020 Infertility: understanding investigation and treatment options. InnovAiT 13 394–401. (https://doi.org/10.1177/1755738020923714)

    • Search Google Scholar
    • Export Citation

  • Lai MS, Cheng YS, Chen PR, Tsai SJ & Huang BM 2014 Fibroblast growth factor 9 activates Akt and MAPK pathways to stimulate steroidogenesis in mouse Leydig cells. PLoS ONE 9 e90243. (https://doi.org/10.1371/journal.pone.0090243)

    • Search Google Scholar
    • Export Citation

  • Li J, Fang B, Ren F, Xing H, Zhao G, Yin X, Pang G & Li Y 2020 TCP structure intensified the chlorpyrifos-induced decrease in testosterone synthesis via LH-LHR-PKA-CREB-Star pathway. Science of the Total Environment 726 138496. (https://doi.org/10.1016/j.scitotenv.2020.138496)

    • Search Google Scholar
    • Export Citation

  • Liao CH, Wang YH, Chang WW, Yang BC, Wu TJ, Liu WL, Yu AL & Yu J 2018 Leucine-rich repeat neuronal protein 1 regulates differentiation of embryonic stem cells by post-translational modifications of pluripotency factors. Stem Cells 36 1514–1524. (https://doi.org/10.1002/stem.2862)

    • Search Google Scholar
    • Export Citation

  • Licatalosi DD 2016 Roles of RNA-binding proteins and post-transcriptional regulation in driving male germ cell development in the mouse. Advances in Experimental Medicine and Biology 907 123–151. (https://doi.org/10.1007/978-3-319-29073-7_6)

    • Search Google Scholar
    • Export Citation

  • Lin D, Sugawara T, Strauss JF, Clark BJ, Stocco DM, Saenger P, Rogol A & Miller WL 1995 Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267 1828–1831. (https://doi.org/10.1126/science.7892608)

    • Search Google Scholar
    • Export Citation

  • Liu H, Yang Y, Zhang L, Liang R, Ge RS, Zhang Y, Zhang Q, Xiang Q, Huang Y & Su Z 2014 Basic fibroblast growth factor promotes stem Leydig cell development and inhibits LH-stimulated androgen production by regulating microRNA expression. Journal of Steroid Biochemistry and Molecular Biology 144 483–491. (https://doi.org/10.1016/j.jsbmb.2014.09.016)

    • Search Google Scholar
    • Export Citation

  • Lu H & Cao X 2008 GRIM-19 is essential for maintenance of mitochondrial membrane potential. Molecular Biology of the Cell 19 1893–1902. (https://doi.org/10.1091/mbc.e07-07-0683)

    • Search Google Scholar
    • Export Citation

  • Maier D 2019 The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis. Hereditas 156 5. (https://doi.org/10.1186/s41065-019-0081-0)

    • Search Google Scholar
    • Export Citation

  • Marei WF, Abayasekara DR, Wathes DC & Fouladi-Nashta AA 2014 Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion. Reproductive Biomedicine Online 28 388–400. (https://doi.org/10.1016/j.rbmo.2013.11.005)

    • Search Google Scholar
    • Export Citation

  • Martin LJ & Tremblay JJ 2010 Nuclear receptors in Leydig cell gene expression and function. Biology of Reproduction 83 3–14. (https://doi.org/10.1095/biolreprod.110.083824)

    • Search Google Scholar
    • Export Citation

  • Miller WL & Auchus RJ 2011 The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews 32 81–151. (https://doi.org/10.1210/er.2010-0013)

    • Search Google Scholar
    • Export Citation

  • Murta D, Batista M, Trindade A, Silva E, Henrique D, Duarte A & Lopes-da-Costa L 2014 In vivo Notch signaling blockade induces abnormal spermatogenesis in the mouse. PLoS ONE 9 e113365. (https://doi.org/10.1371/journal.pone.0113365)

    • Search Google Scholar
    • Export Citation

  • Payne AH & Hales DB 2004 Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine Reviews 25 947–970. (https://doi.org/10.1210/er.2003-0030)

    • Search Google Scholar
    • Export Citation

  • Santos RM, Moreno C & Zhang WC 2020 Non-coding RNAs in lung tumor initiation and progression. International Journal of Molecular Sciences 21 2774. (https://doi.org/10.3390/ijms21082774)

    • Search Google Scholar
    • Export Citation

  • Sharpe RM & Fraser HM 1983 The role of LH in regulation of Leydig cell responsiveness to an LHRH agonist. Molecular and Cellular Endocrinology 33 131–146. (https://doi.org/10.1016/0303-7207(8390162-4)

    • Search Google Scholar
    • Export Citation

  • Sun P, Nallar SC, Kalakonda S, Lindner DJ, Martin SS & Kalvakolanu DV 2009 GRIM-19 inhibits v-Src-induced cell motility by interfering with cytoskeletal restructuring. Oncogene 28 1339–1347. (https://doi.org/10.1038/onc.2008.480)

    • Search Google Scholar
    • Export Citation

  • Sun P, Nallar SC, Raha A, Kalakonda S, Velalar CN, Reddy SP & Kalvakolanu DV 2010 GRIM-19 and p16INK4a synergistically regulate cell cycle progression and E2F1-responsive gene expression. Journal of Biological Chemistry 285 27545–27552. (https://doi.org/10.1074/jbc.M110.105767)

    • Search Google Scholar
    • Export Citation

  • Tai P & Ascoli M 2011 Reactive oxygen species (ROS) play a critical role in the cAMP-induced activation of Ras and the phosphorylation of ERK1/2 in Leydig cells. Molecular Endocrinology 25 885–893. (https://doi.org/10.1210/me.2010-0489)

    • Search Google Scholar
    • Export Citation

  • Tammineni P, Anugula C, Mohammed F, Anjaneyulu M, Larner AC & Sepuri NBV 2013 The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. Journal of Biological Chemistry 288 4723–4732. (https://doi.org/10.1074/jbc.M112.378984)

    • Search Google Scholar
    • Export Citation

  • Tang H, Brennan J, Karl J, Hamada Y, Raetzman L & Capel B 2008 Notch signaling maintains Leydig progenitor cells in the mouse testis. Development 135 3745–3753. (https://doi.org/10.1242/dev.024786)

    • Search Google Scholar
    • Export Citation

  • Tremblay JJ 2015 Molecular regulation of steroidogenesis in endocrine Leydig cells. Steroids 103 3–10. (https://doi.org/10.1016/j.steroids.2015.08.001)

    • Search Google Scholar
    • Export Citation

  • Tripathy MK, Ahmed Z, Ladha JS & Mitra D 2010 The cell death regulator GRIM-19 is involved in HIV-1 induced T-cell apoptosis. Apoptosis 15 1453–1460. (https://doi.org/10.1007/s10495-010-0527-3)

    • Search Google Scholar
    • Export Citation

  • Yang Y, Cheng L, Wang Y, Han Y, Liu J, Deng X & Chao L 2017 Expression of NDUFA13 in asthenozoospermia and possible pathogenesis. Reproductive Biomedicine Online 34 66–74. (https://doi.org/10.1016/j.rbmo.2016.10.001)

    • Search Google Scholar
    • Export Citation

  • Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S, Wu GS & Wu K 2015 Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Letters 369 20–27. (https://doi.org/10.1016/j.canlet.2015.07.048)

    • Search Google Scholar
    • Export Citation